Haystack 2011 Year-in-Review
Jan03

Haystack 2011 Year-in-Review

Well, 2011 is in the books, and we here at The Haystack felt nostalgic for all the great chemistry coverage over this past year, both here and farther afield. Let’s hit the high points: 1. HCV Takes Off – New treatments for Hepatitis C have really gained momentum. An amazing race has broken out to bring orally available, non-interferon therapies to market. In October, we saw Roche acquire Anadys for setrobuvir, and then watched Pharmasset’s success with PSI-7977 prompt Gilead’s $11 billion November buyout.  And both these deals came hot on the heels of Merck and Vertex each garnering FDA approval for Victrelis and Incivek, respectively, late last spring. 2. Employment Outlook: Mixed – The Haystack brought bad employment tidings a few times in 2011, as Lisa reported. The “patent cliff” faced by blockbuster drugs, combined with relatively sparse pharma pipelines, had companies tightening their belts more than normal. Traffic also increased for Chemjobber Daily Pump Trap updates, which cover current job openings for chemists of all stripes. The highlight, though, might be his Layoff Project.  He collects oral histories from those who’ve lost their jobs over the past few years due to the pervasive recession and (slowly) recovering US economy.. The result is a touching, direct, and sometimes painful collection of stories from scientists trying to reconstruct their careers, enduring salary cuts, moves, and emotional battles just to get back to work. 3. For Cancer, Targeted Therapies – It’s also been quite a year for targeted cancer drugs. A small subset of myeloma patients (those with a rare mutation) gained hope from vemurafenib approval. This molecule, developed initially by Plexxikon and later by Roche / Daiichi Sankyo, represents the first success of fragment-based lead discovery, where a chunk of the core structure is built up into a drug with help from computer screening.From Ariad’s promising  ponatinib P2 data for chronic myeloid leukemia, to Novartis’s Afinitor working in combination with aromasin to combat resistant breast cancer. Lisa became ‘xcited for Xalkori, a protein-driven lung cancer therapeutic from Pfizer. Researchers at Stanford Medical School used GLUT1 inhibitors to starve renal carcinomas of precious glucose, Genentech pushed ahead MEK-P31K inhibitor combinations for resistant tumors, and Incyte’s new drug Jakifi (ruxolitinib), a Janus kinase inhibitor, gave hope to those suffering from the rare blood cancer myelofibrosis. 4. Sirtuins, and “Stuff I Won’t Work With  – Over at In the Pipeline, Derek continued to chase high-profile pharma stories. We wanted to especially mention his Sirtris / GSK coverage (we had touched on this issue in Dec 2010). He kept up with the “sirtuin saga” throughout 2011, from trouble with duplicating life extension in model organisms to the...

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The Right Kinase
Sep09

The Right Kinase

Today I posted a news story about the debut of the structure of PLX4032, a promising melanoma drug developed by Berkeley, California startup Plexxikon. This drug's story has already been given the narrative treatment courtesy of the New York Times. And when the results of a Phase I clinical trial of PLX4032 came out, it got covered in many other news outlets as well. But we here at The Haystack are most interested in PLX4032's chemical backstory. And when I contacted kinase expert Kevan M. Shokat for his opinion on the work, he said the story has another dimension- clues about how to pick the right kinase targets to treat diseases. The kinase enzyme that Plexxikon's experimental drug targets is called B-RAF. It's part of a critical signaling pathway that also includes the kinases MEK and ERK. What's interesting about Plexxikon's stunningly successful early trial (81% of patients taking PLX4032 saw their tumors shrink) is just how well people tolerate the drug, Shokat says. The patients in that 81% success group were taking almost a gram of the stuff, twice daily. This is despite the obvious central importance of the RAF-MEK-ERK pathway, and in contrast to what happens when you block MEK, just one step down the pathway, Shokat says. Compounds that block MEK tend to have what's called a narrow therapeutic index- there's a small window between giving an effective dose and giving a toxic one, he says. So if researchers could understand why such a dramatic difference exists, it could help them make the right kinase choices for other diseases as well, he says. When I spoke with Plexxikon's senior VP of research, Gideon Bollag, he too had interesting things to say about kinases, but our discussion was less about choosing one kinase out of many and more about making the commitment to choosing one at all. "Over the last 10 years or so many of the drugs for cancer have been multitargeted kinase inhibitors, and I think our compound is changing that paradigm," he says. "More selective compounds can be more effective because you can dose higher levels safely," he...

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